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A FDA Staff Discussion on Endovascular
Medical Devices Intended to Treat
Intracranial Aneurysms
Neurological Devices Advisory Panel Meeting March 1, 2018
Presentations By: Samuel Raben, Ph.D. and Patrick Noonan, Jr., M.D. Contributors: Neurointerventional Devices Branch (NIDB) in the Division of
Neurological and Physical Medicine Devices (DNPMD) Office of Device Evaluation (ODE)
Center for Devices and Radiological Health (CDRH) U.S. Food and Drug Administration (FDA)
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Purpose of Current Panel Meeting The purpose of this panel meeting is to discuss, make recommendations, and advise FDA regarding the evaluation of clinical study data to assess the risks and benefits of intracranial aneurysm treatment devices and factors that can affect clinical outcomes such as aneurysm morphology, size, and location in the neurovasculature.
Additionally, FDA is also convening this committee to seek expert opinion on the scientific and clinical considerations relating to the clinical trial design that may be relevant to the determination of safety and effectiveness for these devices.
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Presentation Outline Purpose Cerebral Aneurysm Overview Aneurysm Treatment Methods Evaluating the Risks and Benefits of Aneurysm
Treatments
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April 2015 Advisory Committee Meeting Purpose was to obtain feedback on clinical and statistical
considerations for clinical trial design evaluating intracranial aneurysm devices.
Summary of Panel recommendations o Randomized controlled trials should always be considered,
unless determined not to be feasible. o If performance goal (PG) based study is the only option, the PGs
should be well justified and matched to the patient population studied.
o One year follow up for these studies is reasonable for a premarket decision and 5 year follow up may be needed for postmarket data collection of long term adverse effects.
o Aneurysms can be grouped into small/medium and large/giant with respect to risk and benefit profile in addition to considerations for anterior vs. posterior circulation, perforator rich regions, and aneurysm morphology.
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Cerebral Aneurysm Overview: Diagnosis and Characteristics
Samuel Raben, PhD Mechanical Engineer
CDRH/ODE/DNPMD/NIDB
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Morphology of Cerebral Aneurysms Saccular aneurysms protrude from a side wall (most common) Fusiform is a dilation of the vessel Dissection is the result of a tear between the vessel wall
layers. Wide Neck
Defined as neck width 4 mm or a dome to neck ratio < 2
Saccular Fusiform Dissection Hopkinsmedicine.org
Dome
Neck
Wide-Neck
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http:Hopkinsmedicine.org
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Anatomical Locations Typically occur at or near
vessel branch points or bifurcations
Aneurysm occur more frequently in the anterior circulation Anterior ~85%90% Posterior ~10%15%
Patient outcomes can be influenced by aneurysm location.
[Wikipedia]
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The Role of Perforators in Interventional Treatment
Perforators are small branches that emerge from large vessels that supply blood to various regions of the brain
Exist in both the anterior and posterior circulation
Can be affected by open surgical and endovascular treatment methods
o Based on the endovascular treatments/device, it may affect the risk of perforator occlusion differently
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Cerebral Aneurysm Size Aneurysms sizes can vary Small aneurysms occur most frequently
Size Range Occurrence (n=1449)
Small < 5 mm 47%
Medium 6-10 mm 27%
Large
Giant
11-25 mm
> 25 mm
12%
14%
(Wiebers 1998) 9
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Risk Factors for Aneurysm Rupture Difficult to predict the risk of aneurysm rupture.
Risk factors can include, but not limited to, family history, history of prior subarachnoid hemorrhage (SAH), gender, smoking, location of aneurysm, morphology, and overall size.
Rupture Rate over 5 years (n=4060)
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Aneurysm Treatment Methods
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Regulatory Pathways Premarket Notification
(510(k)) Clearance Standard: o Substantial equivalence to a predicate device General controls Special controls
Humanitarian Device Exemption (HDE) Approval Standard: o Probable benefit outweighs risk from the use of the device Requires local IRB approval Less than or equal to 8,000
patients per year
Premarket Approval (PMA) Approval Standard: oReasonable assurance of safety & effectiveness General and special controls
alone are insufficient to assure the safety and effectiveness
De Novo Granting Standard: oReasonable assurance of safety & effectiveness General controls Special controls
FDA works with Sponsors to tailor the scientific and clinical evidence to support approving a device for marketing in the U.S. typically along one of four pathways shown.
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Cerebral Aneurysm Treatments
Endovascular Treatment Coiling Balloon Assisted Coiling (BAC) Stent Assisted Coiling (SAC) Flow Diversion (FD) Intrasaccular Flow Disruption
Open Surgery (Craniotomy) Direct Clipping
Medical Management Observation
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Neurovascular Embolization Coiling
SNIS.org
Technology Typically made of metal Consists of framing, filler, and finishing coils to pack the aneurysm sac
Possible Benefits Less invasive than open surgery Controlled filling of the aneurysm sac and may be more amenable to treat
various aneurysm shapes Possible Risks/Limitations
Not suitable to treat wide-neck aneurysms Longer procedural time to fill aneurysm sac with multiple coils
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http:SNIS.org
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Balloon Assisted Coiling (BAC)
Technology Balloon catheter inflating across the
aneurysm neck Procedural use with traditional neurovascular
embolization coils Possible Benefits
Increase coil density with no vessel implant Complication rates similar to traditional
coiling Possible Risks/Limitations
May not work with all aneurysm neck sizes (i.e., wide-neck aneurysms)
Pierot (2012) AJNR
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Stent Assisted Coiling (SAC) Technology
Self expanding stent placed Stent
Coils permanently in the vessel to hold neurovascular embolization coils within the aneurysm sac
Possible Benefits Treatment of wide-neck aneurysms
MayfieldClinic.com Possible Risks/Limitations Unknown long term risks and
effectiveness Permanent implant Must be used with antiplatelet
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http:MayfieldClinic.com
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Flow Diverters Technology
High mesh density metal stent permanently placed in the vessel to divert blood flow from entering the aneurysm sac
Possible Benefits Can treat wide-neck aneurysms Used as a stand-alone device Shorter procedural time
Possible Risks/Limitations Narrow approved Indication for Use Interaction with perforators not well understood Delayed effect of aneurysm securement until
endothelialization takes place Must be used with antiplatelet therapy
Flow Diverter
MayfieldClinic.com
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Intrasaccular Flow Disruption Technology
o Devices placed into the aneurysm sac designed to seal the aneurysm neck from blood flow entering the aneurysm and promote thrombosis.
o Intended to be a stand-alone device Possible Benefits
o No permanent implant in the vessel lumen. o Single device implant vs. multiple embolization coils o Shorter procedural time o Can treat bifurcation and wide-neck aneurysms
Possible Risks/Limitations o May only be suitable to treat a limited subset of aneurysm sizes and
types based on device design o Long term risks and effectiveness unknown o Limited re-treatment options and retreatment risks unknown
Currently no intrasaccular flow disruption devices on the US market. 18
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Open Surgical Clipping
Bafound.org
Technology Aneurysm clip(s) placed across the neck of the aneurysm
Possible Benefits Provide complete and immediate occlusion
Possible Risks/Limitations Open surgical risks and longer hospital stays Not all are surgically accessible 19
http:Bafound.org
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Conservative Medical Management Aneurysm Observation
Regularly scheduled follow up imaging assessments for aneurysm growth or morphological changes
Reduction of rupture risk factors Blood pressure control Reduce/eliminate smoking
Possible Benefits No surgical or device-related risks
Possible Risks/Limitations Patient preference Not well understood risk of aneurysm rupture
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Summary of Treatment Options Different treatment approaches can have different risk
benefit profiles
Treatment options can vary based on aneurysm characteristics (e.g., size, location in the neurovasculature, morphology, wide-neck)
Understanding the benefits and risk of different treatment options is a major focus of this Advisory Committee meeting, and how the current clinical landscape can be applied to the review of clinical data of new aneurysm devices
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Evaluating the Benefits and Risks of Aneurysm Treatments
Patrick Noonan, Jr., MD Interventional Neuroradiologist, Medical Officer
CDRH/ODE/DNPMD/NIDB
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Benefit Risk Assessment 1. The uncertainty in the benefits and the risks; 2. Characterization of the disease; 3. Patient tolerance for risk and perspective on their
benefit; 4. The availability of alternative treatments or diagnostics; 5. Any risk mitigation strategies available; 6. The possibility of obtaining post-market data that
improves the information about device outcomes; and 7. Whether a device represents a novel technology that
addresses an unmet medical need.
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Evaluating Potential Benefits and Risks of
New Aneurysm Treatment Devices
Limitations may exist in determining which aneurysms are best treated with each treatment modality based upon the clinical data collected
Many factors may be considered in evaluating benefit-risk of new devices including: Device designs Limitation of clinical study data Patient population studied (aneurysm characteristics) Ruptured versus unruptured aneurysms Follow up duration Safety and effectiveness endpoints Rate of adverse events and aneurysm occlusion
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Regulatory Considerations and Levels of Evidence
L. Pierot et al. AJNR 2012 SNIS.org
universityneurosurgery.com
Neurovascular Embolization Coils, BAC, Aneurysm Clips 510(k) Pathway Substantial Equivalence Numerous Devices Marketed in US
MayfieldClinic.com
Flow Diverter
MayfieldClinic.com
SAC - Humanitarian Device Exemption (HDE) Safety & Probable Benefit 4 Devices Approved in US Neuroform EZ, 3, ATLAS
(H020002) Enterprise VRD (H060001) LVIS (H130005)
Flow Diverter - Premarket Approval (PMA) Safety & Effectiveness 1 Device Approved in US Pipeline & Pipeline Flex
Embolization Device (P100018)
Increasing Level of Evidence to Support Marketing Approval in US
PulseRider (H160002)
Mostly performance standards (e.g., nonclinical in Small human
safety clinical Well controlled human pivotal clinical trials (e.g., prespecified
vitro and/or in vivo studies) trials (e.g., ~ hypothesis testing, endpoints, 30 subjects) multicenter, statistically justified
sample size) 25
http:universityneurosurgery.comhttp:SNIS.org
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Valid Scientific Evidence
Per 21 CFR 860.7(c)(2), valid scientific evidence is evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use.
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A Sample of Clinical Trial Designs Hierarchy of Clinical Trial Designs
Randomized Controlled Trial
Non-Randomized Controlled Trial
Single-Arm Performance Goal (PG)
Study
Retrospective Study Descriptive Study
Case Series
Lowest Level of Uncertainty
Highest Level of Uncertainty
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Study Design Considerations
July 9, 2012 Revision of FDA Safety and Innovation Act IDE studies cannot be disapproved based on
study design issues.
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Primary Endpoints for Safety and Effectiveness
Safety Rate of neurological deaths and major ipsilateral
strokes defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) 4 points from baseline during the stroke event
Effectiveness Percent of subjects who achieve complete (100%)
Raymond I classification without significant artery stenosis ( 50%) or retreatment of the target aneurysm
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Secondary Endpoints Safety/Effectiveness
Modified Rankin Scale (mRS) Surgical technical success and device placement Retreatment and use of adjunctive devices Recurrence of target aneurysm Procedural time Radiation exposure
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Serious Adverse Events (SAEs) Associated with Aneurysm Treatment Devices
Minor strokes Transient ischemic attacks Subarachnoid hemorrhage Device migration Dual antiplatelet therapy (DAPT) related adverse events Access site issues Delayed aneurysm rupture
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Adequate Aneurysm Occlusion
[R.S. Quadros et al. ANJR 2007]
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Follow-Up Duration
Balancing Pre-/Post-Market Review
Premarket FDA decisions have been made with 1 year
follow-up data for PMAs and 6 months follow-up for HDEs
Postmarket Clinical studies have consented subjects to 5
years of follow-up if post-approval studies or long-term follow-up is needed as a condition of approval of the marketing application
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Labeling Labeling is important to provide information
about the product, including the indicated patient population.
Labeling may be used to clarify to users the
evidence in support of a medical device.
Labeling can also link to the type of data collected.
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Closing Remarks The purpose of todays public meeting is to discuss and
obtain Panel advice regarding the evaluation of clinical study data to assess the potential benefits and risks of intracranial aneurysm treatment devices and factors that can affect clinical outcomes such as aneurysm morphology, size, and location in the neurovasculature.
Listen to multiple stakeholders on additional factors important in assessing the benefit/risk relationship for evaluating aneurysm treatment devices.
Later this afternoon, we look forward to the Panels recommendations regarding aneurysm treatment devices to support FDAs mission to ensuring U.S. patients have access to high-quality, safe, and effective medical devices of public health importance first in the world.
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Thank You
Questions?
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Slide Number 1Purpose of Current Panel MeetingPresentation OutlineApril 2015 Advisory Committee MeetingSlide Number 5Morphology of Cerebral AneurysmsAnatomical LocationsThe Role of Perforators in Interventional TreatmentCerebral Aneurysm SizeRisk Factors for Aneurysm RuptureSlide Number 11Regulatory PathwaysCerebral Aneurysm TreatmentsNeurovascular Embolization CoilingBalloon Assisted Coiling (BAC)Stent Assisted Coiling (SAC)Flow DivertersSlide Number 18Open Surgical ClippingConservative Medical ManagementSummary of Treatment OptionsSlide Number 22Slide Number 23Evaluating Potential Benefits and Risks of New Aneurysm Treatment DevicesRegulatory Considerations and Levels of EvidenceSlide Number 26Slide Number 27Study Design ConsiderationsPrimary Endpoints for Safety and Effectiveness Secondary EndpointsSerious Adverse Events (SAEs) Associated with Aneurysm Treatment DevicesAdequate Aneurysm OcclusionFollow-Up Duration Balancing Pre-/Post-Market ReviewLabelingClosing RemarksThank You Questions?